chr19-12647289-A-C

Variant names:

• chr19-12647289-A-C
• rs768233248
• NM_000528.4:c.2867T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_Strong PP5

The NM_000528.4(MAN2B1):​c.2867T>G​(p.Leu956Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MAN2B1 NM_000528.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:3
• Conservation: PhyloP100: 6.25
• Publications: 3 publications found

Genes affected

MAN2B1 (HGNC:6826): (mannosidase alpha class 2B member 1) This gene encodes an enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. Its activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover and it is member of family 38 of glycosyl hydrolases. The full length protein is processed in two steps. First, a 49 aa leader sequence is cleaved off and the remainder of the protein is processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). Next, the 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Defects in this gene have been associated with lysosomal alpha-mannosidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

MAN2B1 Gene-Disease associations (from GenCC):

• alpha-mannosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ENSG00000269242 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 19-12647289-A-C is Pathogenic according to our data. Variant chr19-12647289-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 208280.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000528.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	NM_000528.4	MANE Select	c.2867T>G	p.Leu956Arg	missense	Exon 23 of 24	NP_000519.2
	MAN2B1	NM_001440570.1		c.2870T>G	p.Leu957Arg	missense	Exon 23 of 24	NP_001427499.1
	MAN2B1	NM_001173498.2		c.2864T>G	p.Leu955Arg	missense	Exon 23 of 24	NP_001166969.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAN2B1	ENST00000456935.7	TSL:1 MANE Select	c.2867T>G	p.Leu956Arg	missense	Exon 23 of 24	ENSP00000395473.2
	MAN2B1	ENST00000221363.9	TSL:1	c.2864T>G	p.Leu955Arg	missense	Exon 23 of 24	ENSP00000221363.4
	ENSG00000269242	ENST00000597692.1	TSL:2	n.425T>G		non_coding_transcript_exon	Exon 3 of 5	ENSP00000470240.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251474 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461880 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.000206 Hom.: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	3	-	Deficiency of alpha-mannosidase (7)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		6.2
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.92		Gain of MoRF binding (P = 0.0064)
MVP		0.99
MPC		1.1
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs768233248; hg19: chr19-12758103;